Carrageenan viscoelastics for ocular surgery

ABSTRACT

Disclosed are carrageenan-based transitional viscoelastics that will induce little or no IOP spike when left in the eye at the close of surgery thereon. Drug delivery systems for delivering therapeutic agents during post-operative recovery stages are also disclosed.

This application claims the benefit of Provisional Application No.60/246,236, filed Nov. 6, 2000.

FIELD OF THE INVENTION

The present invention relates to the field of viscous and viscoelasticmaterials suitable for use in surgical procedures. In particular,transitional viscoelastics (having non-shear related variableviscosities) comprising carrageenans, which may be left iii situ at theclose of surgery, are disclosed. Methods of using transitionalviscoelastics in surgery, especially ophthalmic surgery are alsodisclosed.

BACKGROUND OF THE INVENTION

Viscous or viscoelastic agents used in surgery may perform a number ofdifferent functions, including without limitation maintenance andsupport of soft tissue, tissue manipulation, lubrication, tissueprotection, and adhesion prevention. It is recognized that the differingrheological properties of these agents will necessarily impact theirability to perform these functions, and, as a result, their suitabilityfor certain surgical procedures. See, for example, U.S. Pat. No.5,273,056.

Cataracts are opacities of the ocular lens which generally arise in theelderly. In order to improve eyesight, the cataractous lens issurgically removed and an artificial intraocular lens is inserted in itsplace. During these surgical procedures, viscoelastic materials aretypically injected in the anterior chamber and capsular bag to preventcollapse of the anterior chamber and to protect tissue from damageresulting from physical manipulation.

A number of viscous or viscoelastic agents (hereinafter “agents”) areknown for ophthalmic surgical use. For example, Viscoat® (AlconLaboratories, Inc.) which contains sodium hyaluronate and chondroitinsulfate; Healon® and Healon® GV (Pharmacia Corp.), Amvisc® Regular andAmvisc® Plus (IOLAB), and Vitrax® (Allergan) all of which contain sodiumhyaluronate; and Cellugel® (Alcon) which containshydroxypropylmethylcellulose (HPMC) are all useful in cataract surgery.They are used by the skilled ophthalmic surgeon for several purposes:maintenance of the anterior chamber of the eye and protection ofophthalmic tissues during surgery, particularly corneal endothelialcells, and as an aid in manipulating ophthalmic tissues.

While all of the agents described above may be used during cataractsurgery, each has certain recognized advantages and disadvantages. See,U.S. Pat. No. 5,273,056. Generally, however, all such agents havingsufficient viscosity and pseudoplasticity to be useful in ophthalmicsurgery will, if left in the eye at the close of surgery, result in atransient increase in intraocular pressure (“IOP”) known as an “IOPspike.” (See, Obstbaum, Postoperative pressure elevation. A rationalapproach to its prevention and management, J. Cataract RefractiveSurgery 18:1 (1992).) The pressure increase has been attributed to theagent's interference with the normal outflow of aqueous humor throughthe trabecular meshwork and Schlemm's canal. (See, Berson et al.,Obstruction of Aqueous Outflow by Sodium Hyaluronate in Enucleated HumanEyes, Am. J. Ophthalmology 95:668 (1983); Olivius et al.,Intraocularpressure after cataract surgery with Healon®, Am. IntraocularImplant Soc. J. 11:480 (1985); Fry, Postoperative intraocular pressurerises: A comparison of Healon, Amvis, and Viscoat, J. CataractRefractive Surgery 15:415 (1989).) IOP spikes, depending on theirmagnitude and duration, can cause significant and/or irreversible damageto susceptible ocular tissues, including, without limitation, the opticnerve.

Thus, the ease with which an agent can be removed from the surgicalsite, typically by aspiration, has traditionally been considered animportant characteristic in the overall assessment of the agent'susefulness in cataract surgery. By removing the agent before the closeof surgery, the surgeon hopes to minimize or avoid any significant IOPspike. Unfortunately, however, removal of agents which are relativelydispersive (as opposed to cohesive) or which adhere to the ocular tissueis often difficult and may cause additional trauma to the eye.

Exogenous dilution of the viscoelastic has been suggested to alleviateIOP spikes. See U.S. Pat. No. 4,328,803. Depending, however, on theparticular viscoelastic and the surgical technique employed, IOP spikemay still be a problem. More recently, it has been suggested that theadministration of degradative agents to break down conventional viscousor viscoelastic agents in the eye can reduce or avoid the occurrence ofIOP spikes. See, e.g., U.S. Pat. No. 5,792,103. Such an approachrequires not only the administration of a second, enzymatic agent intothe eye, the biocompatibility of which must be assured; but also meansfor adequately mixing the two agents in a special apparatus.

Viscoelastics have also been promoted as drug delivery devices forpharmaceutical agents which are administered when the viscoelastics areapplied during surgery. For example, U.S. Pat. No. 5,811,453 (Yanni etal.) discloses viscoelastics containing anti-inflammatory compounds andmethods of using these enhanced viscoelastics in cataract surgery. Whilethis approach may ameliorate ocular inflammation resulting from surgicaltrauma, such an approach still possesses the significant limitation ofpresenting IOP spike problems, as described above. Consequently, theseenhanced viscoelastics still need to be aspirated out at the close ofsurgery.

There is, therefore, a need for an improved means for reducing oravoiding IOP spikes associated with the use of conventional viscous orviscoelastic agents in ophthalmic surgery, especially cataract surgery.More specifically, we conceived the need for an improved viscous orviscoelastic agent having a variable or transitional viscosity such thatit will, without the addition of degradation agents, becomesubstantially less viscous after its purpose has been served in surgery,such agents being hereinafter referred to as transitional viscoelastics.Such transitional viscoelastics may then be left by the surgeon to beeliminated gradually from the surgical site by the body's naturalprocesses without creating a dangerous IOP spike.

Transitional viscosities are known to occur in certain agents systems.In the ophthalmic field, systems are known in which a liquid forms a gelafter application to the eye. For example, such gelations may betriggered by a change in pH. See, Gurney et al., “The Development andUse of In Situ Formed Gels, Triggered by pH” Biopharm. Ocul. DrugDelivery, (1993) pp. 81–90. Temperature sensitive gelation systems havealso been observed for certain ethyl (hydroxyethyl) cellulose ethers(EHECs) when mixed with particular ionic surfactants at appropriateconcentrations. See, Carlsson et al., “Thermal Gelation of NonionicCellulose Ethers and Ionic Surfactants in Water” Colloids Surf., volume47, pages 147–65 (1990) and for systems of pure methylethyl cellulose,U.S. Pat. No. 5,618,800 (Kabra et al.)) Likewise, gellan gum (Gelrite®)is known to form a gel on contact with specific cations. Greaves et al.,“Scintigraphic Assessment of an Ophthalmic Gelling Vehicle in Man andRabbit,” Curr. Eye Res., volume 9, page 415 (1990). Gellan systems havebeen suggested for use as a vehicle for ophthalmic medications (Rozieret al., “Gelrite: A Novel, Ion-Activated, In Situ Gelling Polymer forOphthalmic Vehicles. Effect on Bioavailability of Timolol,” Int. J.Pharm., volume 57, page 163 (1989)), and one gellan system is currentlybeing marketed with timolol, a beta blocker, as a glaucoma medication.Carrageenans also have been suggested for use as a delivery vehicle forophthalmic drugs. See, e.g. U.S. Pat. Nos. 5,403,841 and 5,965,152, thecontents of both of which are by this reference incorporated herein.U.S. Pat. No. 5,403,841 and EP0 424043 disclose ophthalmic carrageenancompositions which transition from liquid to gel when topically appliedto the eye. Finally, it is known that carrageenans can be tailored toadjust their viscosity transitions to different temperature ranges.(See, Verschueren et al. “Evaluation of various carrageenans asophthalmic viscolysers” STP Pharma Sci., volume 6, pages 203–210 (1996),and Picullel et al., “Gelling Carragreenans,” Food Polysaccharides andtheir Applications, Ed: Stephen, A. M., Marcel Dekker: New York, volume67, pages 204–44 (1995).) Kappa-carrageenans, for example, arepolysaccharides which display a temperature dependent conformationwherein at high temperature the molecules exist as random coils. As thetemperature is lowered, the chains associate into double helices, and,depending on the amount of potassium (K⁺) in the solution, the doublehelices then self-associate into a three dimensional network. The gelformed by potassium cross-linked kappa-carrageenan is, unfortunately,very brittle, resembling the gels formed by calcium cross-linkedalginate and pectin. All of these gels also exhibit syneresis, a processwherein the formation of the gel is so favored that the solvent(physiologic aqueous media here) is forced out from the gel network.

The use of a transitional viscosity viscoelastic agent as an effectivesurgical tool, however, especially in ophthalmic surgery, has neitherbeen disclosed or suggested in the art. To be effective for use as anophthalmic surgical tool, the agent, in addition to having the desiredinitial and transitional viscosities over the prescribed temperaturerange, would need to meet the following requirements: physiologicallyacceptable osmolarity and pH; relatively short viscosity transitiontime; clear (without turbidity); biocompatible; and sterilizable. Thetransitional viscoelastics of the present invention are believed tosatisfy these requirements

SUMMARY OF THE INVENTION

The present invention is directed to improved viscous or viscoelasticagents for use in surgical procedures, especially ophthalmic surgicalprocedures. The improved agents of the present invention are stable,transitional viscous or viscoelastic carrageenan solutions suitable foruse in ophthalmic surgery, which maintain high viscosity during thesurgical procedure, but rapidly lose viscosity after the close ofsurgery. This rapid loss of viscosity effectively reduces or avoids theoccurrence of dangerous IOP spikes, and obviates the need for activeremoval at the end of the surgical procedure.

Appreciating that the surface temperature of the eye tissues duringsurgery will approximate surgical room temperature, we have discoveredstable agents that will maintain suitable viscosity at that temperature,but will rapidly lose viscosity at a slightly higher temperature (i.e.,body temperature). The loss of viscosity, which occurs without theaddition of a degradation agent, results from the warming of the eyeback to body temperature after the surgery is complete.

DETAILED DESCRIPTION OF THE DRAWINGS

FIG. 1 is graph depicting the transitional viscosity of Carrageenan (80%kappa/20% iota) solutions of the present invention having differentpotassium concentrations, over a range of temperatures.

FIG. 2 is graph depicting the transitional viscosity of Carrageenan (80%kappa/20% iota) solutions of the present invention compared tocommercially available viscoelastic products.

FIG. 3 is graph depicting viscosity versus shear rate for Carrageenan(80% kappa/20% iota) solutions of the present invention.

FIG. 4 is a graph depicting viscosity versus shear rate for autoclavedand unautoclaved Carrageenan (80% kappa/20% iota) solutions of thepresent invention.

FIG. 5 is a graph depicting viscosity versus temperature for 0.8%Carrageenan solutions of the present invention with variable kappa/iotaratios.

FIG. 6 is a graph depicting data from a constant stress oscillationexperiment using 0.7% Carrageenan solutions of the present invention.

FIG. 7 is a graph depicting data from a constant frequency oscillationexperiment using 0.7% Carrageenan solutions of the present invention.

FIG. 8 is a graph depicting viscosity versus temperature for solutionsof 0.7-wt% kappa-carrageenan in a phosphate buffered saline (PBS) with0%, 0.2%, 0.4%, 0.7% and 0.8% chondroitin sulfate.

DETAILED DESCRIPTION OF THE PRESENT INVENTION

The present invention is directed to substantially stable, transitionalviscoelastic materials, compositions and methods of use.

The primary use of the transitional viscoelastics is in surgicalapplications where the transitional viscoelastic is applied duringsurgery in its more viscous state and, following surgery, losessubstantial viscosity in situ. A preferred use of the transitionalviscoelastics is in cataract surgery, where the viscoelastic isinstilled in the anterior chamber of the eye to maintain the dome andprotect the exposed tissues. Following surgery, the viscoelastic isheated by the body to ambient body temperature, loses its viscosity, andis more readily removed (than non-transitional viscoelastics) by theeye's processes. The major advantage of this preferred use is theavoidance of the IOP spike present in other systems. Thus, anotheradvantage of this use is that it allows the surgeon the traditionaladvantages of a viscoelastic without the disadvantage of having toaspirate the viscoelastic out of the surgical site following completionof the surgery. As stated above, such aspiration is time consuming andpresents additional risk to the patient.

The transitional viscoelastics of the present invention are typicallymodified viscoelastics exhibiting a viscosity loss of 80% or more, whensuch materials undergo a temperature change of from about roomtemperature or surgical temperature (approximately 17–26° C.) to aboutbody temperature (approximately 35–38° C.).

The transitional property of the present invention viscoelastics ispreferably reversible. The reversible viscosity property of thepreferred embodiments allows the transitional viscoelastics to be heatedprior to use, e.g., heat sterilization, and then recooled for surgicalapplication.

While bound by no theories, we postulate that the transitionalviscoelastic character of the compositions of the present invention maybe attributable to physical associations between relatively lowmolecular weight molecules resulting in a viscosity beyond what would beexpected from such low molecular weight molecules at a givenconcentration. The viscosity of the presently claimed viscoelasticsolution goes through a transition in the intraocular environment andbecomes a free flowing aqueous solution. As a result, the subjectviscoelastic solution can pass through the trabecular meshwork of theeye, resulting in its excretion from the anterior segment, with no orsignificantly reduced intraocular pressure spike.

Kappa-carrageenan is a polysaccharide which displays a temperaturedependent conformation wherein at high temperature the molecules existas random coils. As the temperature is lowered, the chains associateinto double helices, and, depending on the amount of K⁺ in the solution,the double helices then self-associate into a three dimensional network.The gel formed by potassium cross-linked kappa-carrageenan, while usefulas a transitional viscoelastic, is relatively brittle and elasticcompared to commercially available viscoelastics, and resembles the gelsformed by calcium cross-linked alginate and pectin. All of these gelsalso exhibit a degree of syneresis, a process wherein the formation ofthe gel is so favored that the solvent (physiologic aqueous media here)is forced out from the gel network.

Surprisingly, it has been discovered that the previously describeddeficiencies of kappa carrageenan as a transitional viscoelastic may beovercome by blending it with one or more related polymers, preferablybeing pharmaceutically acceptable sulfated polysaccharides. In apreferred embodiment, kappa- and iota-carrageenan are mixed in order toreduce syneresis and the brittle nature of the kappa-carrageenan gels.The iota-carrageenan competes with the kappa-carrageenan for potassium,resulting in a more viscous and less brittle gel, while retaining adesirable transitional profile.

The kappa carrageenan and other sulfated polysaccharides of the presentinvention will have the weight average molecular weight ranges set forthin the following table:

Preferred MW Polysaccharide MW Range (M_(W)) Range (M_(W))Kappa-Carrageenan 25–900 kDa 50–400 kDa Iota-Carrageenan 100–3,000 kDa400–700 kDa Chondroitin sulfate 10–100 kDa 20–60 kDa Heparin 2–50 kDa6–30 kDaPreferred concentrations for the kappa-carrageenan constituent, alone ormixed with another sulfated polysaccharide such as iota-carrageenan,fall in the range of 0.3 to 1.5 weight percent. Overall viscosity isdirectly dependent on the concentration used. The carrageenans, bothkappa and iota, are commercially available from FMC Corporation, FoodIngredients Division, Rockland, Me.

For mixtures, the ratio of kappa to iota will preferably be in the rangeof 40 to 90% kappa to 10 to 60% iota (i.e. from about 4:6 to about 9:1)to preserve the beneficial transitional properties of the kappaconstituent and the viscous gel imparting properties of the iotaconstituent. The potassium-level should not exceed 0.10% on aweight-to-volume basis in an aqueous media based on balanced saltsolution with citrate/acetate buffer or a NaCl solution with phosphatebuffers. The level of potassium will modulate the transitiontemperature, and should be chosen so that the transition is essentiallycomplete by 35 degrees Celsius.

The carrageenan solutions. of the present invention are autoclavable atexposure for at least 60 minutes, without appreciable reduction of theirtransitional viscoelastic character. Such solutions will preferably loseat least 90 percent of their pre-transition viscosity and mostpreferably at least 99% upon heating through the transition. Asdescribed herein, the transition temperature range will depend upon andmay be controllably shifted by varying the potassium level. Preferredviscosity transition ranges, however, will be from about 17–26° C. onthe lower end, to about 35–38° C. on the upper end. Most preferred is atransition temperature range from about 25° C. to about 37° C.

A unique aspect of the transitional viscoelastics of the presentinvention is that they possess a variable transition temperature range.The transition temperature is affected, and thus controllable, by theamount of potassium present. Furthermore, the magnitude of thetransition, in terms of viscosity loss through the transition, is muchgreater than has been reported with hydrophobically modified materials.These materials are also steam autoclavable, and achieve usefulviscosities with relatively short polysaccharide chains andconcentrations of 1% or less.

The following exemplify some of the preferred kappa-/iota-carrageenantransitional viscoelastics of the present invention.

EXAMPLE 1

Solutions of 0.5 wt % carrageenan (80% kappa-/20% iota-) were made inPBS with 0% to 0.070% KCl. These samples were heated to above thetransition temperature and hot filtered through a 5 micron filter. Thesolutions were cooled and then subjected to 50 passes through a dual hubsyringe connector. Rheological data was then collected, and viscosityversus temperature data is shown in FIG. 1. The figure shows that theeffect of increasing levels of potassium is to increase thepre-transition viscosity and to increase the transition temperature.Potassium ions appear to have little or no effect on the post-transitionviscosity.

EXAMPLE 2

Solutions with a total of 80% kappa-carrageenan and 20% iota-carrageenanwere made in phosphate buffered saline. The total solids of thesolutions ranged from 0.6 wt % to 0.8 wt %. FIG. 2 shows the viscosityversus temperature Theological curves for these mixtures. The curves forPROVISC® product and for VISCOAT® product are also included as controls.The figure shows that increased solids content increases both thepre-transition viscosity and the transition temperature itself. The 0.7wt % and the 0.8 wt % samples are viscosity matched to the VISCOAT® andPROVISC® curves at 28° C., respectively. PROVISC® and VISCOAT® loseabout 33% of their viscosity over the range shown in the figure. Inmarked contrast, the 0.7 and 0.8% carrageenan gels lose more than 99.9%of their viscosity over the transition range from approximately 34° C.to approximately 40° C.

EXAMPLE 3

Solutions of carrageenan (80% kappa-/20% iota) were made at 0.5%, 0.6%,0.7% and 0.8% in PBS and hot filtered and homogenized as above. FIG. 3shows the viscosity versus shear rate dependencies for these samples.The figure shows a general increase in viscosity with increased levelsof carrageenan in the solution. Interestingly, the viscosity of the 0.5%solutions are much lower than the other samples. The 0.5% samples didnot gel to the extent of the higher weight percent samples.

EXAMPLE 4

A solution of a 0.9 wt % carrageenan (80% kappa-/20% iota-) was preparedin PBS and hot filtered and homogenized as above. This solution wassplit into two samples, one of which was subjected 30 minutes exposureat approximately 121° C. in a steam autoclave. FIG. 4 shows these twosamples to display little variation in their rheological behavior asevidenced by the plot of viscosity versus shear rate. The curve for theautoclaved sample is generally below the control curve; however, theTheological properties of the autoclaved material are still in the veryuseful range.

EXAMPLE 5

Solutions with a total of 0.8 wt % carrageenan were made in phosphatebuffered such that the ratio of kappa-carrageenan to iota-carrageenanincluded solutions with 0%, 20%, 40%, 60%, 80% and 100% of kappa-, withthe remainder being the percent of iota-. FIG. 5 shows the viscosityversus temperature Theological data in the pre-transition, thetransition, and the post-transition regions. The data support the ideathat pre-transition viscosity is higher with higher percentages ofiota-carrageenan. The data also support the idea that the transitiontemperature is lower with higher percentages of kappa-carrageenan andthat the more iota- in the mixture, the more drawn out the later stagesof the transition are. Based upon this figure, it is felt that too muchiota raises the transition temperature and causes a tailing off of theviscosity at the end of the transition region. Thus, the iota contentpreferably should be less than 60 percent to preserve the transitiontemperature of the kappa- portion of the mixture. The iota contentshould further be minimized to reduce the tailing off of the viscosityat the end of the transition. However, the iota- content makes the gelmore viscous and less elastic, or brittle, in nature. A balance betweenkappa- and iota- will depend on the total solids content used. At thistotal concentration, the best gels were produced at 60% kappa- and 40%iota-.

EXAMPLE 6

Samples of carrageenan at 0.7% solids were made with 50% and 100% kappa-were made in PBS and hot filtered and homogenized as above. FIG. 6 showsan oscillatory experiment performed at constant stress over a largefrequence range. At a frequence of 1.29 Hz, the ratio of G″ to G′, inpercent form, was shown to be 12.4% for the 100% kappa- and 23.4% forthe 50% kappa-. This result shows that the gel with the mix of kappa-and iota- displays more viscous (G″) character than the 100% kappa-.

EXAMPLE 7

Samples of carrageenan at 0.7% solids were made with 50%, 60% and 100%kappa- were made in PBS and hot filtered and homogenized as above. FIG.7 shows an oscillatory experiment performed at constant frequency over alarge strain range. At a strain of 0.01, the ratio of G″ to G′, inpercent form, was shown to be 8.9%, 20.0%, and 22.5% for the 100%, 60%and 50% samples, respectively. This data also shows that the addition ofiota- is directly related to the increase in viscous behavior and thedecrease in elastic behavior.

Alternatively, the transitional viscoelastics of the present inventionmay comprise combinations of chondroitin sulfate and a transitionalviscoelastic agent or agents.

The primary advantage of combining chondroitin sulfate with transitionalviscoelastic agent lies in the ability of chondroitin sulfate to coatand protect biological tissues. In particular, the ability ofchondroitin sulfate to coat the interior tissues of the eye duringocular surgery gives added protection. For example, during cataractsurgery, chondroitin sulfate can coat and protect the cornealendothelium during the phacoemulsification process, which exposes theinterior tissues of the eye to high ultrasound power, which can causetissue damage. The corneal endothelium is especially important to visionsince this layer of cell is vital in regulation of corneal hydrationlevel and maintenance of the stable refractive power of the cornea.Since this tissue is not regenerated, damage to the corneal epithelialcell can cause a permanent loss in vision. As such, protection of thecorneal endothelium is, therefore, also vital to a favorable outcome tocataract surgery.

Surprisingly, it has been discovered that the previously describeddeficiencies of kappa-carrageenan as a transitional viscoelastic may beovercome by blending it with other sulfated polysaccharides, such aschondroitin sulfate and heparin. While bound by no theories, it isbelieved that the sulfated polysaccharide competes with thekappa-carrageenan for potassium via its sulfate groups, resulting in amore viscous and less brittle gel. Therefore, in the case oftransitional viscoelastics based on kappa-carrageenan, an additionaladvantage in the use of chondroitin sulfate is found beyond the abilityof chondroitin sulfate to coat and protect biological and ocular tissuesmentioned above.

Therefore, the preferred transitional viscoelastics of the presentinvention will be mixtures of chondroitin sulfate and transitionalviscoelastic materials, such as, kappa-carrageenan alone or admixed withiota-carrageenan. The transitional viscoelastic agents will preferablyhave molecular weights from about 50,000 Daltons to about 400,000Daltons (weight average molecular weight). Preferred concentrations forthe kappa-carrageenan component, fall in the range of about 0.3 to about1.5 weight percent. While the preferred concentration of chondroitinsulfate in these transitional viscoelastic formulations is from about0.5 to about 4%. Overall viscosity is directly dependent on theconcentration used.

The viscosities of the transitional viscoelastic formulations based onkappa-carrageenan in combination with chondroitin sulfate are alsomodulated by the presence of potassium ion. The potassium level shouldnot exceed 0.10% on a weight to volume basis in an aqueous media basedon balanced salt solution with citrate/acetate buffer or a NaCl solutionwith phosphate buffers. The level of potassium will modulate thetransition temperature, and should be chosen so that the transition tominimum viscosity is essentially complete by 35° C.

Chondroitin sulfate is commercially available from Seika GakuCorporation, Tokyo, Japan.

The effect of adding chondroitin sulfate to these kappa-carrageenanformulations, i.e. thereby increasing the overall concentration, is toreduce the elastic character as stated above. However, chondroitinsulfate will also provide small increases in pre-transition viscosityand small decreases in the transition temperature.

The following exemplify some of the preferredkappa-carrageenan/chondroitin sulfate embodiments of the presentinvention.

EXAMPLE 8

Solutions of 0.7-wt % kappa-carrageenan were made in phosphate bufferedsaline (PBS) with 0%, 0.2, 0.4, 0.7 and 0.8% chondroitin sulfate. Thesesamples were heated to above the transition temperature and hot filteredthrough a 5-micron filter and transferred to syringes. The solutionswere cooled and then subjected to 150 passes through a dual hub syringeconnector. Rheological data was then collected, and viscosity versustemperature data is shown in FIG. 8. The figure shows that the effect ofincreasing levels of chondroitin sulfate is to essentially maintain thepre-transition viscosity and to decrease the transition temperature.Chondroitin sulfate appears to have little or no effect on thepost-transition viscosity.

EXAMPLE 9

Solutions with kappa-carrageenan/chondroitin sulfate levels of0.4%/0.5%, 0.5%/0.4%, 0.6/0.3% and 0.7%/0.2%, such that each had a totalviscoelastic content of 0.9% were made in phosphate buffered saline(PBS). These samples were heated to above the transition temperature andhot filtered through a 5-micron filter and transferred to syringes. Thesolutions were cooled and then subjected to 150 passes through a dualhub syringe connector. Rheological data was then collected, andviscosity versus temperature data is shown in FIG. 8. The figure showsthat decreasing the ratio of kappa-carrageenan of chondroitin sulfatedramatically reduced the pre-transition viscosity and transitiontemperature. The 0.5% kappa-/0.4% chondroitin sulfate formulation was aviscoelastic gel rather than a brittle gel. In the absence ofchondroitin sulfate, 0.4% and 0.5% kappa-carrageenan form brittle gels.

EXAMPLE 10

In order to quantify the effect of chondroitin sulfate on the viscousand elastic nature kappa-carrageenan/chondroitin sulfate viscoelasticformulations, oscillatory rheology was carried out. As demonstrated inthe table below, the complex viscosity of carrageenan/chondroitinsulfate formulations (in this case having a 0.9 wt. % total solidscontent) decreases as the proportion of kappa-carrageenan in theformulation is decreased. Also the in the table below is a calculationfor G″/(G′+G″)×100%, where G″ is the viscous modulus and G′ is theelastic modulus. This constant frequency (1.3 Hz) experiment is carriedout at 0.01 strain. The calculation shows that the viscous nature of thegel increased as the proportion of chondroitin sulfate in the mixture isincreased.

TABLE Calculation of Complex Viscosity from Oscillatory RheologyExperiment Complex Viscosity: % Formulation Composition ViscousCharacter = % Kappa-carrageenan % Chondroitin Sulfate {G″/(G′ + G″)} ×100 0.4 0.5 61% 0.5 0.4 33% 0.6 0.3 11.5 0.7 0.2 11.0The 0.7% kappa-/0.2% chondroitin and 0.6% kappa-/0.3% chondroitinformulations show about 11% viscous character; however, when theformulation contains 0.5% kappa-/0.4% chondroitin sulfate, the viscouscomponent rises to 33%. Finally, when the formulation contains 0.4%kappa-/0.5% chondroitin sulfate, the viscous component rises to 61%.

Those skilled in the art will appreciate that the suitability of a giventransitional viscoelastic for a particular step in a surgical procedurewill depend upon such things as the viscoelastic's concentration,average molecular weight, viscosity, pseudoplasticity, elasticity,rigidity, adherence (coatability), cohesiveness, molecular charge, andosmolality in solution. The viscoelastic's suitability will dependfurther on the function(s) which the viscoelastic is expected to performand the surgical technique being employed by the surgeon.

An appropriate buffer system (e.g., sodium phosphate, sodium acetate orsodium borate) may be added to the compositions to prevent pH driftunder storage conditions.

Because all or a significant portion of the transitional viscoelasticsof the present invention may be left in the eye at the close of surgery,these viscoelastics are uniquely adapted to serve the dual roles ofviscosurgical tool and drug delivery device.

Ophthalmic drugs suitable for use in the compositions of the presentinvention include, but are not limited to: anti-glaucoma agents, such asbeta-blockers including timolol, betaxolol, levobetaxolol, andcarteolol; miotics including pilocarpine; carbonic anhydrase inhibitors;prostaglandin analogues including latanoprost, travoprost, andbimatoprost; seratonergics; muscarinics; dopaminergic agonists;adrenergic agonists including apraclonidine and brimonidine;anti-infective agents including quinolones such as ciprofloxacin, andaminoglycosides such as tobramycin and gentamicin; non-steroidal andsteroidal anti-inflammatory agents, such as suprofen, diclofenac,ketorolac, rimexolone and tetrahydrocortisol; growth factors, such asEGF; immunosuppressant agents; and anti-allergic agents includingolopatadine. The ophthalmic drug may be present in the form of apharmaceutically acceptable salt, such as timolol maleate, brimonidinetartrate or sodium diclofenac. Compositions of the present invention mayalso include combinations of ophthalmic drugs, such as combinations of(i) a beta-blocker selected from the group consisting of betaxolol andtimolol, and (ii) a prostaglandin analogue selected from the groupconsisting of latanoprost; 15-keto latanoprost; fluprostenol isopropylester (especially1R-[1α(Z),2β(1E,3R*),3α,5α]-7-[3,5-dihydroxy-2-[3-hydroxy-4-[3-(trifluoromethyl)-phenoxy]-1-butenyl]cyclopentyl]-5-heptenoicacid, 1-methylethyl ester); and isopropyl[2R(1E,3R),3S(4Z),4R]-7-[tetrahydro-2-[4-(3-chlorophenoxy)-3-hydroxy-1-butenyl]-4-hydroxy-3-furanyl]-4-heptenoate.

In the event a pharmaceutical agent is added to the transitionalviscoelastics, such agents may have limited solubility in water andtherefore may require a surfactant or other appropriate co-solvent inthe composition. Such co-solvents typically include: polyethoxylatedcastor oils, Polysorbate 20, 60 and 80; Pluronic® F-68, F-84 and P-103(BASF Corp., Parsippany N.J., U.S.A.); cyclodextrin; or other agentsknown to those skilled in the art. Such co-solvents are typicallyemployed at a level of from about 0.01 to 2 wt. %. It may also bedesirable to add a pharmaceutically acceptable dye to the viscoelasticto improve visualization of the viscoelastic during surgery and/or tostain ocular tissue (especially the capsular bag during capsulorhexis incataract surgery) for improved visualization of such tissue. The use ofsuch dyes in conventional viscoelastics is described in WO 99/58160.Preferred dyes include trypan blue, trypan red, brilliant crysyl blue,and indo cyanine green. The concentration of the dye in the viscoelasticsolution will preferrably be between about 0.001 and 2 wt. %, and mostpreferably between about 0.01 and 0.1 wt %. However, it Will beappreciated by those skilled in the art that any such additive(pharmaceutical agents, co-solvents, or dyes) may only be employed tothe extent that they do not detrimentally affect the viscoelasticproperties of the compositions of the present invention.

The methods of the present invention may also involve the use of variousviscoelastic agents having different adherent or cohesive properties.Those skilled in the art will recognize that the compositions of thepresent invention may be employed by the skilled surgeon in a variety ofsurgical procedures.

Given the advantages of each type of viscoelastic, the surgeon mayemploy is various viscoelastic compositions of the present invention ina single surgical procedure. While the use of the transitionalviscoelastic of the present invention have not been disclosed for use insurgeries, U.S. Pat. No. 5,273,056 (McLaughlin et al.) discloses methodswhich exploit the use of compositions employing viscoelastics of varyingviscoelastic properties during a given ocular surgery, the entirecontents of which are incorporated herein by reference.

For example,. for portions of surgical procedures involvingphacoemulsification and/or irrigation/aspiration, e.g., cataractsurgery, it is generally preferable to use a viscoelastic agent thatpossesses relatively greater adherent properties and relatively lessercohesive properties. Such viscoelastic agents are referred to herein as“adherent” agents. The cohesiveness of a viscoelastic agent in solutionis thought to be dependent, at least in part, on the average molecularweight of that agent. At a given concentration, the greater themolecular weight, the greater the cohesiveness. Those portions ofsurgical procedures involving manipulation of delicate tissue aregenerally better served by viscoelastic agents that possess relativelygreater cohesive properties and relatively lesser adherent properties.Such agents are referred to herein as “cohesive” agents. For cohesiveagents such as these, which are being employed primarily for tissuemanipulation or maintenance purposes as opposed to protective purposes,a functionally desirable viscosity will be a viscosity sufficient topermit the skilled surgeon to use such agent as a soft tool tomanipulate or support the tissue of concern during the surgical step(s)being performed.

For other viscoelastic agents, which are being employed primarily forprotective purposes (“adherent” agents) as opposed to tissuemanipulation purposes, a functionally desirable viscosity will be aviscosity sufficient to permit a protective layer of such agent toremain on the tissue or cells of concern during the surgical step(s)being performed. Such viscosity will typically be from about 3,000 cpsto about 60,000 cps (at shear rate of 2 sec⁻¹ and 25° C.), andpreferably will be about 40,000 cps. Such adherent agents are capable ofproviding the protective function previously discussed, yet are notprone to inadvertent removal, which could jeopardize the delicate tissuebeing protected. Unfortunately, this same characteristic makesaspiration of such adherent viscoelastics at the end of surgery (asrecommended for all such commercially available products in cataractsurgery), problematic for surgeons, and subjects the coated tissues totrauma during the removal procedure. A significant advantage of thetransitional viscoelastics of the present invention is that they may beleft in the surgical site at the close of surgery thereby avoidingunnecessary trauma to the affected soft tissues.

Preferred methods of the present invention will employ the use ofmultiple viscoelastics in a given surgical procedure, wherein at leastone of such viscoelastics is a transitional viscoelastic. In a mostpreferred embodiment of the invention, a transitional viscoelasticpossessing superior adherent properties is used in cataract surgery, atthe close of which some or all of it is left in situ and causes littleor no IOP spike.

The invention has been described by reference to certain preferredembodiments; however, it should be understood that it may be embodied inother specific forms or variations thereof without departing from itsspirit or essential characteristics. The embodiments described above aretherefore considered to be illustrative in all respects and notrestrictive, the scope of the invention being indicated by the appendedclaims rather than by the foregoing description.

1. A transitional viscoelastic composition for use in surgery,comprising a sterile, non-inflammatory, aqueous solution comprisingkappa-carrageenan, potassium, and a second sulfated polysaccharide, suchsolution having a viscosity transition temperature range from 17–26° C.to 35–38° C., wherein such solution exhibits a loss of viscosity of atleast 80% upon heating through such viscosity transition temperaturerange.
 2. The composition of claim 1, wherein the viscosity transitiontemperature range is from about 25° C. to about 37° C., and wherein thesecond sulfated polysaccharide is selected from the group consisting of:chondroitin sulfate, heparin, and combinations thereof.
 3. Thecomposition of claim 2, wherein the second sulfated polysaccharide ischondroitin sulfate and the weight ratio of the kappa-carrageenan to thechondroitin sulfate is from about 4:5 to about 7:2.
 4. The compositionof claim 3, wherein the combined concentration of the kappa-carrageenanand the chondroitin sulfate is from about 0.9 to about 1.5 wt %.
 5. Atransitional viscoelastic composition for delivering an ophthalmic drugto an affected eye, comprising the ophthalmic drug in a sterile, aqueoussolution comprising kappa-carrageenan, potassium, and a second sulfatedpolysaccharide, such solution having a viscosity transition temperaturerange from 17–26° C. to 35–38° C., wherein such solution exhibits a lossof viscosity of at least 80% upon warming through such viscositytransition temperature range.
 6. The composition of claim 5, wherein theviscosity transition temperature range is from about 25 to about 37° C.and wherein the ophthalmic drug is selected from the group consistingof: anti-glaucoma agents; anti-infective agents; steroidal andnon-steroidal anti-inflammatory agents; growth factors;immunosuppressant agents; anti-allergy agents, and combinations thereof.7. A method of protecting, manipulating or stabilizing tissue in an eyeduring surgery thereon, comprising instilling in the eye a transitionalviscoelastic composition comprising a sterile, non-inflammatory, aqueoussolution comprising kappa-carrageenan, potassium, and a second sulfatedpolysaccharide, such solution having a viscosity transition temperaturerange from 17–26° C. to 35–38° C., wherein such solution exhibits a lossof viscosity of at least 80% upon warming through such viscositytransition temperature range.
 8. The method of claim 7, furthercomprising the step of allowing a protecting or stabilizing effectiveamount of the transitional viscoelastic to remain in the eye at theclose of the surgery.
 9. The method of claim 7, wherein the secondsulfated polysaccharide is selected from the group consisting of:iota-carrageenan, chondroitin sulfate, heparin, and combinationsthereof.
 10. The method of claim 9 wherein the second sulfatedpolysaccharide is iota-carrageenan and the weight ratio of thekappa-carrageenan to the iota-carrageenan and is from about 2:3 to about9:1.
 11. The method of claim 10, wherein the weight ratio ofkappa-carrageenan to iota-carrageenan is about 3:2.
 12. The method ofclaim 11, wherein the combined concentration of the kappa-carrageenanand the iota-carrageenan is about 0.8 wt %.
 13. The method of claim 9,wherein the second sulfated polysaccharide is chondroitin sulfate andthe weight ratio of kappa-carrageenan to chondroitin sulfate is fromabout 4:5 to about 7:2.
 14. The method of claim 13, wherein the combinedconcentration of the kappa-carrageenan and the chondroitin sulfate isfrom about 0.9 to about 1.5 wt %.
 15. The method of claim 7, wherein thesurgery is cataract surgery.